Synthesis of vitamin a



Patented Feb. 13,

New YorbfN. IL, a sar srnrnasrs orvrramn a Nicholas" A. .Milas, Belmont, .Mass; Research Corporation,

' 1 poration oi New York V I No Drawint. Application March 2', i942,

alsl nor' to Serial No. 433,233

3 Claims. (Cl. 260-617) The general object of the present invention is to provide a novel process for the synthetic production of vitamin A and a number of related intermediate products.

The accepted chemical structure of vitamin A is represented by the formula:

It readily may be seen that vitamin A, as well as other antixerophthalmic carotenoids (antixerophthalmic pro-vitamins), are related to B-ionone which is a well known substance used as an important ingredient in the synthesis of perfumes.

'Ihe first step in my process consistsin the condensation of p-ionone with ethyl chloroacetate (see Equation A) in the presence of solid anhydrous sodium ethylate, using anhydrous toluene or benzene as solvents, thereby producing Compound II, Equation A.

CH: CH:

it e...

Compound Ila which reacts with the sodium ethylate yielding Compound II.

v glycidic acid, Compound III, Equation B, is sep- In the second step, Compound is saponiiled with 10% alcoholic potash and the resulting arated and" decarboxylated by distillation to promethyl buten-1-al-4, Compound IV, Equation 'C.

EQUATIOF B on, em

I v OBI I a n A} I a KOH C=C -.CCOOH Compound 11+ Alcohol a CH:

qampouadlll' E UATION C CH: om CHI' 1 v Distillation H .C=C -C'=0+C0a- CompoundIIl-l- --v I H a on, 1

I i i 'ompwndI V n Compound IV maybeprepared alsolby condensing gin an ethereal solution; fl-ionone with v ethyl dichloroacetate (ChCHCOOCaH l in; the

, presence of dilute magnesium amalgam; yielding Compound IIa, Equation D, whichilatter maybe saponifled with alcoholic potash and the resulting. saponifi'cation produce decarboxylated to Product .IV as in Equations B and C.

EQUATION D I CHI OH:

I CIIICHCOOCSHI B Monone I cal with the intermediate product of Equation A and when this Product 11a is subjected to saponification with alcoholic KOH as in Equation B, it is simultaneously or successively converted into Compound II and Compound III. Y

Instead of decarboxylating Compound III by distillation as described above, Compound III is mixed with two molecular equivalents of pyridine and the resulting pyridine salt distilled under a pressure of about 1 mm. and the fraction distilling at about from C. to 103 0. (Compound IVa) collected; This fraction (Compound IVa) serves in the remainder of the process described hereinafter in the same way as Compound IV but evidence, such as its boiling point, spectroscopic examination, and absence of aldea an 5 a o=o- --c-cooc.m

- Compound IV-l- 1k inliquid NH: H: CH:

hydic properties, indicates that it is not. Compound IV but a compound or the formula CH: CH:

CH: H H J: H H C=C- -CH v H: CH:

CompoundIVa In the third step, Compound IV or Compound IVa is condensed with sodium or lithium acetylide in a mixture of anhydrous ether and liquid ammonia at temperatures between -55 and -70 C. -After the reaction is over, the ammonia is removed and the product treated with a dilute solution of tartaric acid, although aqueous solutions of ammonium sulfate, ammonium chloride or other organic acids may also be used. The resulting Compound V or Compound Va, Equations E and Ea, is extracted from this mixture in an impure state and may be purified either by high vacuum distillation in an inert atmosphere or by preparing its phthalic acid ester by reacting the mixture with phthalic anhydride in pyridine solution; The phthalic acid ester is subsequently sa-- ponified to obtain the pure acetylene carbinol Compound V or Compound Va.

EQUATION E CH: CH: CH:

' H H NBCECH H -C--C-:CH

Compound V EQUATION EA CH; OH;

NaCECH H Compound IVa -v in liquid NH:

H: I OH: H

Compound Va EQUATION F a Compound 1V HCECMgX Compound V or or Compound IVa Compound Va (X stands for halogen) In the fourth step, Compound V or Va may be dehydrated by distilling under high vacuum with small amounts of naphthalene sulfonic acid or ptoluene sulfonic-acid yielding Compound VII directly see Equation G) EQUATION G vacuum distillation dehydrating v catalysts Thus it will be seen vthat both Compounds IV and Wu maybe treated in the same manner to yield Compound VII.

However, better yields of Compound VII are ob- Compound V Compound VII (see Equatlon I) or Compound Va tained by preparing from Compounds V and Va the halides thereof, Compounds VI and VIa, Equations H and Ha, and subsequently removing hydrogen halide with alcoholic potash (see Equa 6 tions I and Ia).

EQUATION H CH; CH:

CH: PX: H -JJ %C=CB 10 Compound V+ I I Pyridine x CH: v

(in which X is a halogen) Compound V! I Eons-non HA CH: CH:

' CE: I m like-a Jam Compound Va+ U i 11 Pyridine X H: CH:

(in which X is a halogen) Compound VIa It is observed that Equation Ha works best with the chloride, less well with the bromide, and poorly or not at all with the iodide.

80 4 EQUATION I CH: CH:

CH: H H 6 H KOH H C= =C-CECH Compound VI+ -r as Alcohol Q I H: CH:

' Compound VII o EHUATION IA KOH Compound VIa+ -0 Compound Vll alcohol Still another method of converting Compound V or Compound Va into Compound VII is to form the Grignard 01' Compound V having the formula CH: CH:

OH: H H H B I C=CH-C-CECMgX $MBX H: CH:

I (X stands ior halogen) Gri andrd of Compound V or the Grignard of Compound Va having the formula CH2 CH3 OH:

H H a H [I C=C-- -C-CECMgX i l' H H: CH; MEX

(X stands for halogen) In the fifth step the Grignard or alkali metal acetylide of Compound VII is prepared by allowin: it to react in ether solution with ethylmag nesium bromide or metallic lithium, for example:

To the Grignard or alkali acetylide 01' Compound VII is slowly added methyl vinyl ketone whereby the Product VIII is formed (see Equation J).

Equsrron J CH: CH: CH: CH:

11 n n l n n c=o- =CCEC(MgBrH-O= -c=cn.

(Li) CHI CH: CH: CH: CH:

11 n n n C=C- =CCEC C=CH: 4

11 CHI Compound VIII In the sixth step Compound VIII is partially hydrogenated cataLvtically at room temperature using gaseous hydrogen and palladium black catalyst deposited on calcium carbonate or barium sulfate yielding Compound IX, Equation K. Another usetul method for the partial reduction of Compound VIII to produce Compound IX is the use 01' an active iron catalyst, made by leaching with alkali the aluminum from an aluminum-iron alloy, and hydrogen under a pressure of about 50-75 atmospheres and temperatures not higher than 100 C. (see Equation K). Equsrron K HI Compound VIII+ t Pd or active iron CH: CH: CH: (i'lHi n n n H n n n c.=c =c-c= -c=cm Compound IX In the seventh step, Compound IX may be treated with acetic anhydride to form the acetic ester of vitamin A, Compound XI, Equation L.

In this step any suitable acid anhydride other than acetic anhydride, such as propionic and its higher homologues up to and including palmitic and stearic and other organic acid anhydrides, such as benzoic acid anhydride, could be employed to produce the corresponding vitamin A esters, any of which may be converted into vitamin A by saponiflcation, as described hereinafter.

Eons-non L acetic anhydride Compound IX+ Compound XI (see Equation N) Better yields of the acetate are obtained when Compound DI is treated first with a halogenating agent such as phosphorus tribromide in pyridine yielding Compound X, Equation M, which latter is treated with potassium acetate yielding Compound XI, Equation N.

In this step Compound IX may be treated with any other suitable halogenating agent such as phosphorus trichloride or thionyl chloride and the resultinghalogcn Compound x converted into any desired organic acid ester 01 vitamin A by siredacidtinvthepresence'ofthiree acid.

Still another method of making the esters or vitamin A is to treat Compound XV or Compound XVa with acetic or any other suitable organic acid anhydride in the presence of the alkali meta1 salt of said acid and heat the mixture in vacu- 10. um thereby directly producing the acid ester of vitamin A.

CompoundX --0 heat CH1 CH8 The vitamin is finally prepared by saponitying Compound XI, Equation 0, or by treating Com- 40 pound x with silver hydroxide (see Equation P).

Eausrxou O Y ssponiiy 0 slocbolic KOH 60-70 C. in N atmosphere Eausrron P:

0 pound X 7.; in alcoholic solution npto 60 C.

Compound XI Compound I Compound I so In the p p ration of Compound XI. the 101- lowing alternative route may be used: Methyl vinyl ketone is condensed with sodium or lithium acetyllde in liquid ammonia to produce, Compound XII, Equation Q, which latter is then converted as into the Grignard XIII, Equation R, by interaction with ethyl magnesium bromide. The Grignard'xIII is allowed to react in ether solution with the Compound IV or We followed by hydrolysis with tartaric acid or ammonium sulrate to produce Compound XIV or XIVa, Equation 8 or So.

' EQUATION Q HCECNa Eousrrou R CH: H at H:C=C CECMgX MgX (X stands for halogen) I Guam XIII 20a! M x Compound x11 treating it with the alkali meta .Bi lt. f, he, 9?

norm-1on5 Econ-roar UA Gri 1d Va dxm followed by hydrolysis with m I Comp und IV+C0mP I r or (Nndso. CH: CH: CH.

' i n a 11 cm on, n c-c- --c-ccmx+ CH: CHI 3 H n n A: n H n C=C-BCCEC --C=g H on x on n n I CHI 1 V CompowldXIV o-= -cn=cn, XIVa mm by (X stands (or halopn) Compound Iva Compound xm Mm Compound XV or XVa is halogenated with a CH; CHI

Cbmpormd XIV.

Earn-r08 T Pd on ClOOI Ol'BlBOc CH: CH:

Compound XIV Compound X V EdoArroir TA Ha Coin and XIVa p0 catalyst CH: CH

Q 5H H H: CH:

Compound XV An alternative method used to prepare Compound XIV or XIVa consists in the interaction of the Grignard of V or Va with methyl vinylketone (see Equations U and U11) EQUArron U Grignard of V ECMIX+ 0- CHICH| XIV (Insulator-halogen) 15 suitable agent such'as a phosphorus trihalide, e. g. phosphorus trichloride or tribromide in pyri-' dine at 0 C. yielding Compound XVI or XVIa, Equations W and Wu, and the latter are dehydrohalogenated, for example, by treating with exactly one mol of potassium hydroxide in alcohol to yield Compound X, Equation Y.

EauAr-ron W onem on.

at 0 C. H OH:

o x stonds or halogen) Compound XVI;

(The above reactions work better with the chloride than with the bromide.)

EQUArrou Y XVI x01! 0 m ax Xvi: alcohol 0 0 A more detailed account of the principal reactions is to be found in the following pages.

PREPARATION or GLYCID Esrsx Comom 11, Pills Srsr, EQUATION A Twenty-four grams or metallic sodium is dissolved in about 300-400 cc. of absolute ethyl alcohol in a one liter filter flask titted with a reflux condenser. It has-been found preferable to add all of the sodium at once and after it had gone into solution, the alcohol is removed under reduced pressure at temperatures ranging from 160-170". A white sodium ethylate results. This is added slowly to a vigorously stirred mixture of 192 grams of p-ionone, 122 grams, ethyl chloroacetate and 110 cc. of anhydrous toluene (benzene may also be used) at 0. After all of the sodium ethylate had been added, stirring is continued until the mixture becomes homogeneous and brownish in color, then allowed to stand at room temperature for 7- -l0 hours. heated on the water bath tor 5 hours, cooled to room temperature and acidified with acetic acid. The oil separating from this mixture is iractionated under reduced pressure and the frac- It is then and neutralize with asolution of 167 aaeaier tion boiling at 152-185 (H mm.) com. A yield at about of Compolmd II is obtained.

HPII'PAIAHOI- or Couromms III an IV, Smco 7 8m, Eoumoas B m C 4 To obtain Compound m. 10': g. of Compound {I is inixed with one equivalent (21.0 g.) of 10% alcoholie potash and the mixture heated on the water bath for about two hours. The alcohol is then removed under reduced pressure and the residue dissolved in the minimum amount of "water and the aqueous mixture extracted a few times with ether to remove any unsaponiiiable The aqueous solution is then treated with 25% phosphoric acid and the oily layer which separates extracted with ether. The ether extract is then dried with anhydrous magnesium sulfate, filtered and the ether removed under reduced pressure. The residue (Compound III) isbeatedinanatmosphereofnitrogenandin the presence of powdered glass or flnely divided copper to facilitate the removal of carbon dioxide and the aldehyde formed finally fractionatedimderreducedpressureandtheiraction 'boiiing at 143-145 mm.) collectedg'lhls has a 1.5032 and forms a 2,4-dinitrophenylhydraaoue; M. P. 155-157 having the correct ."c'clnbustion analysis.

This aldehyde (Compound IV) has also been PM by the alternative method (Equation D) as part of the second step.

Th -preparation of Compound IVa from Com- -'iioundll1byreactionwith pyridine and distilla- 'tion has been sumciently described above.

l'qll-i m'ethyl S-apo'zy, butane-1 (Compound I76) Wm i To amixture of 245g. (2 racial or ethyl introduce, over a period of two hours-with rapid stirring. 46 g. (2. molslofflnely powdered sodium ethoxide free from alcohol- Bring themixture slowly to room temperature by allowing it to stand overnight with'moderate stirring in an atmos- 1: phere of nitrogen. Continue stirring while the mixture is'heaied in nitrogen-on the water bath for four hours, then cool to room temperature g. of glacial acetic acid in 500 cc. cit-water. The mixture separate into two layers. Remove the'non-a'queous layer and-extract the aqueous layer with two 50 cc. portions of ether and combine the extracts with the non-aqueous layer. Remove the ether and the toluene and other low boiling constitu cuts by subjecting the mixture to a; vacuum distillation (-20 mm.) in an atmosphere oi nitrosec at the temperature of boiling water. Cool the residue (Compound II) to room temperature and 'add to it 840 cc. of 95% alcohol containing 85. g. of potassium hydroxide and reflux the resulting mixture in nitrogen for one hour under a slightly reduced pressure, then remove under reduced pressure approximately two thirds of the alcohol. Cool the residue and pour it into 1500 cc. 01' deoxygenated water and extract the mixture successively with 500, 200 and 150 cc. of ether;.comblue the extracts and wash with 200 cc. of water and combine the latter with the q eous solution. Add to the aqueous layer 200 cc. of fresh ether and acidity with 654 cc. of orthophosphoric acid. Remove ether layer and extract non-aqueous layer successively with 200 and 100 cc. of ether and combine ether extracts; wash ether extracts twice with 110 cc. portions of water, dry over anhydrous magnesium sulfate, fllter and remove ether under reduced pressure. The residue consists of almost Pure ycidic acid (Compound III) containing small amolmis of p-ethoxy acetic acid.

To decarboxylate the glycidic acid dissolve it in 158 g. (2 mols) of pure anhydrous pyridine and subject the mixture to a vacuum distillation in an atmosphere of nitrogen. The pyridine comes over at lower temperatures, then, the residueis fractionated and the fraction boiling at 95-140 (2 mm.) is collected and died as the crude portion of Compound'IVa. This product is found to contain a small amount of an organic acid,

and to remove the latter the product is dissolved in 250 cc. of ether and the ethereal solution shaken vigorously twice with 200 cc. of 5% sodium bicarbonate solution. The ethereal "solution is then dried over magnesium sulfate, filtered, the ether removed imder reduced pressure and the residue fractionatedusingaClaisenflaskattached to a cm. Vigreux column and the fraction boiling at 00-103 (1-2 mm.) collected. n

1.5110, ar 0.940. This product rails to give an aldehyde test with fuchsin reagent and absorption spectrum in the ultra-violet region of the spectrum fails-to show the presence of an aldehyde group eitherisolated from or conJugated with the double bonds.

The large range in boiling point (90-103) .indicates the presence in the product of the cis and trans isomers. The boiling isomer is about 09' to 103'.

Purmrroa or Conroms V m Vs, Damn Srrr,

. ,Equarroxs E arm Es To about 1 l. of liquid ammonia, in a 3-necked flask equip d with a Hershberg stirrer and a. dropping funnel, was added 1 g. of hydrated ferric nitrate and 1 g. of metallic sodium and the mixture stirred for 1 hour while the temperature was kept at to 'l0. To this mixture was then 7 added a trifle excess over half a moi of metallic sodium and the mixture stirred for half an hour longer. Dry acetylene was then passed through the mixture for several hours or until most of the blue color had assumed a gray-white color. To this mixture was then added, in the course of three hours, 46 g. of Compound IV or Compound Na in 200 cc. of anhydrous ether taking care that the temperature of the mixture never rises above ,60' and that the'stirring is very rapid. After all of the aldehyde or oxide had been added, the mixture is stirred for 24 hours longer, keeping the temperatln'e between 55 and 'l0". The ammonia is then allowed to evaporate and the brownish residue treated with excess cold aqueous solution of d-tartaric acid and the resulting mixture extracted with ether from which the acetylene carbinol, Compound V or Compound Va, is isolated either by distillation under high vaculnn (10- mm.) or by preparing its acid point of the major 6 asun er phthalate ester in anhydrous pyridine and subsequently saponifying this ester to obtain the pure acetylene carbinol. The phthalic acid ester had the correct and semi-micro-hydrogenation revealed the presence of 4 double bonds. The acetylene carbinol also gives a heavy whitishgray precipitate with ammoniacal alcoholic silver nitrate solution characteristic for acetylenes.

Compounds V and Va have also been prepared, in anhydrous ether solution, by the interaction of Compounds IV and Na, withthe mono-Grignard of acetylene (HCECMgX), (Equation F).

Purasanox or Coasrounns VI, VIA an VII, FouarnSm,EaumonsH,HamImIs Five 3. of Compound V or Va is dissolved in about 15 g. of anhydrouspyridine and the mixture cooled between and C. To this mixture is slowly added about 2.2 g. of phosphorus tribromide or a corresponding amoimt of phosphorus trichloride taking care that the temperature does not rise about 0'. After halfan hour of standing at 0, the mixture is warmed to about 60-70 for minutes, then. without separating CompoundVIorVIn,themlxtureistreatedwiththe calculated amount plus 10% excess of 10% alcoholic potash. The mixture is heated on the water bath for half an hour. then poured in four times its volume of water. The aqueous mixture is then extracted several times with ether and the ethereal solution shaken a number of times with a solution of d-tartaric acid to remove the pyridine. Finally, the ether solution is dried over anhydrous magnesium sulfate, filtered, and the ether removed. The residue is nearly pure Compound VII. although for further purification one can distillitunderaveryhighvacuum. A

Compmmdvnmsyalsobeprepared y B-r tllling Compound V or Va under reduced pressure (1o-=-1o= mm.) in the presence of small amounts, 1 to 5%, of p-toluene sulfonic acid or naphthalene sulfonlc acid (Equation G). 1

Pssrau'rron or Condom: VIII, Fin-n 8m,

manor J Five g. of Compound VII in cc. of anhydrous ether is slowly added to an ethereal solution of the calculated amount of ethyl magnesium bromide and the mixture refluxed in an atmosphere of nitrogen for 5 to 10 hours. To this mixture is then slowly added at o' with stirring about 2 g. of methyl vinyl ketone which is freshly distilled from small amounts of hydroquinone. The mixture is allowed to stand at room tunperature overnight, then poured onto a mixture of ice and ammonium sulfate. After the Grlgnard mixture is completely hydrolysed, the ethereal layer is separated and dried over anhydrous magnesium sulfate,. filtered, and the ether removed under reduced pressure. The residue which is nearly oure Compound VIII may now be used for the next Step. i

For making Compoimd VIII from Co'mpormd VII via-the alkali metal aceiylide of Compound VII instead of the Grignard thereof, a mixture of equal parts of liquid ammonia and anhydrous ethyl ether is prepared and while being maintained at to C. small equivalent amounts of Compound VII dissolved in anhydrous ethyl ether and metallic lithium areadded while rapidly stirring. After each addition, the blue color produced is permitted to completely disappear before another addition of Compound VII and lithium is made. After the desired amount of Compound VII and the equivalent amount of (I lithium have been'dissolved, a solution of an equivalent quantity of methyl vinyl ketone in anhydrous ethyl ether is added dropwise, in the course of an hour, with continued stirrin and while maintaining the temperature at 60' ,to 'l0 C. The stirring and maintenance of the temperature oi 60 to -'I0' C. is then continued for about 10 hours; after which the temperature isallowedtoriseandtheammoniatoevaporate. 0 The reaction mixtureis then neutralizedwith tartaric acid dissolvedinicecoldwaterandtbe resulting mixture extracted'several times with ethyl ether. The combined ether extracts are dried with anhydrous magnesimn sulfate, then 15 filtered, the ether evaporated imder reduced pressure and the-residue subjected to a vacuum of fromlHtolO-mmofmercurytovaporlwand remove imreacted Compound VII 'and methyl vinylketone. Theresidueofthislasttreatment.

'20onanalysis,conformstotheformulaofCompormd VIII.

Pumas-non or Collrouun 12!, Sum Sm, Eons-non K .25 Compoimd VIII is dissolved in absolute alcohol and to the solution added about one-twentieth oftheweightof Compoundllmof 1% palladhun black deposited onsolid powdered carbonate made in accordance with methods described in the so literature. Bariinn sulfate may be advanta- 35 then iilteredandthetiltratedistilledundermod- -erately reduced pressure. The residue is nearly pureCompoundIX.

ThereductionofCompoundvmtoCompolmd lxmayaisobeaccomplishedunderso-fiahnoslllpheresof hydrogen atnothighcrthanlolrc.

andinthepreseuceofanactlveironcatllnt preparedbyleachingtheahnninnmfiomanirmalmninmnalloy (BquationK).

-PIIPAIATIOH or Condom! III, San-m 8m,

Eouarronsllmli AithoughCompoundxImaybepreparedbythe treatmentofCmnpolmdIxwithaceflcanhydride (Equation L), better yields are obtained by dissolving Compoimd 1K in anhydrous pyridine, coolingtooflandaddingthecalculatedamountof phosphorus tribromide, Equation ll, taking care thatthetemperaturedoesnotrlseaboveo'. The

mixtureisthenwarmedtomomtempuatureand kepttherefortwohours. Themixtureisthm flmagnesimnsulfateandfllteremtheetherisremovedunderreducedpressureandtheresldue Compound X, Equation M, is dissolved in glacial aceticacid and treated,inanaimosphereofnii:ugen, with freshly fused potassium acetate, EqualltionN. Themixtureisgcntlyheatedforabout 2hourstonothigherthan1o0'c.,thenpouredm coidwateraudextractedwithether. Theethereal solutionisseparated.dried,andtheethcrre moved. The residue contains considerable 7o amoimt of Compound XIfromwhichvitaminA can be easily prepared by sapmifyiug it in the usual manner with alcoholic potash (Equation 0). liowevencompoundxlmaybemeddirectly asavitaminasubstitute. l

This application is a contlnuatkm-m-part of whichcompriseg reacting an acetylide ot a compound of the formula CH: CH:

H CHI with methyl vinyl ketone by mixing them in a 1 mutual solvent, and partially reducing the acetylenic linkage of the resulting compound by hydrogenation.

2. Process of producing a compound of the formula which comprises reacting the lithium ot a compound of the formula CHI CH:

acetylide with methyl vinyl ketone by mixing them in a mutual solvent, and partially reducing the acetylenic linkage of the resulting compound by bydrogenation.

7 a0 3. As a new product a compound of the formula n cm mcnomsn m. 

